The TDP dies like most dies consist of 3 pieces that even though are separate work as one:

Upper Punch

Centre Ring

Lower Punch

To successfully change the die that's currently in the machine, you will need to remove all three parts before reassembling the press with the new tooling. You can also use this guide if you want to clean your dies. It's the same principle, but instead of inserting a new die, you clean the tooling you removed and put it back in.

What you will need

Allen keys (different sizes)

Monkey wrench/spanners (22mm and 24mm)

Grease

Pliers

HEALTH AND SAFETY PRECAUTIONS

Please wear suited clothes and plug off the machine completely.

STEP 1 - Ejection tray

The first thing is to remove the ejection tray (2), to have easy access. Do this by unscrewing the two Phillips head screws (1), one on either side.

STEP 2 -Remove the base plate

2.1. Remove the boot timing bar

You need to work to separate the base plate (9) from the machine, so first unscrew the set screw (3) of the Boot Timing Bar (or arm) (5) and then the main screw (4) which holds it in place. Gently remove it being careful not to let the wheel at the top fall out. Keep the wheel together with the Boot Timing Bar

2.2. Boot

Remove the metal boot (8) located to the right of the die assembly, too. Use an Allen key to remove the boot’s central locking nut (6). It is very small so sometimes it gets missed but it’s important to be able to detach the boot.
Then release the boot by loosening the securing nut (7) beneath the plate. Pliers or metal grips will make this easier.

2.3 - Lowering the lower punch die

Finally, lower the lower punch as much as you can by turning the cogs anti-clockwise that is underneath the lower die. For this, remove the bar to the right of the cogs, so you can turn them. This will allow you to take the base plate that holds the centre ring and gain access to the lower punch.

Sometimes you Will need to slightly and carefully shake the base plate and move it upwards so that it comes off easily.

STEP 3 - Take the dies out

3.1. Centre die

There is a locking bolt on the front of the base plate that you will need to loosen to be able to Remove the centre ring.

3.2. Lower punch and upper punch

There is another locking bolt (10) holding the lower punch, also located at the front of the machine at the height of the lower punch, remove this and pull out the punch die.

To remove the upper punch, there is a nut (11) that you will need to loosen. Use one 22mm spanner to loosen it and another 24mm spanner to hold the hexagon part above it in place.

STEP 4 - Insert the new dies

4.1. Centre ring

Place the die in the free hole of the base plate and Secure it by screwing the locking bolt. It’s always good to put some grease around it to ensure easy extraction next time around.

4.2. New upper and lower punches

Insert the lower punch and lock it with the Bolt you previously took off.
Put the new upper punch and lock it by tightening the nut that will secure it in place.

STEP 5 - Mount the machine

Now is the time to revert what you have done previously and put back the base plate, ejection height locking bar, boot and arm. Follow the steps backwards and make sure everything is correctly locked before using the machine.
When putting the base plate back, be careful with the lower punch so that it’s not damaged when you fit it inside the centre die.

And you’re done! Congratulations!

Now you can use your desktop tablet press with the new die assembly. The best is to use it first manually and adjust the settings before you turn the machine on. This will save you from damaging the machine or the tablets.

If you have any more questions, we have tutorial videos in our video section https://www.lfatabletpresses.com/videos and a customer service team who will try their best to assist you.
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Wed, 03 Oct 2018 11:26:51 +0000https://www.lfatabletpresses.com/articles/tablet-manufacturing-dehumidifier
Even the simplest form of pharmaceutical manufacturing process can involve a range of process steps before the product is packaged and shipped to the consumer.These may include:

Lab-scale development using glove boxes, process driers and coaters

Micronising mills

Storage of powders and liquids

Mixing

Tablet compression

Film or sugar coating

Aseptic packaging

Blister packaging

Storage of the finished product

In each of these steps, humidity of the surroundings can have a profound effect on the product appearance, quality, yield and lifetime.Control of humidity is important to achieve a quality product. Whilst some products may be able to be produced with minimal control of workplace humidity, others cannot simply be produced without careful control of the humidity around the process steps.Such control may also vary according to the season and local micro-climate variations.

Conventional HVAC

It is generally easy to maintain the working environment to a temperature around 21 °C and relative humidity near 45%, using refrigeration based air handling systems.Such systems operate using chilled water or direct expansion of a refrigerant and are the basis of traditional heating, ventilation and air conditioning (HVAC) equipment.Modern systems employing electrical compressors use variable speed drives which also permit more accurate control over the ambient conditions compared with earlier thermostat (on/off) systems. Unfortunately at humidity levels around 40% some condensation of airborne moisture around the cooling coils can lead to frozen water building up which reduces the air flow and necessitates regular de-frosting of the equipment. If this is required, humidity control is lost, which is unacceptable for a commercial process that may be running 24/7.

Low humidity

To secure an environment with relative humidity less than about 40% requires different dehumidification technology.The most preferred approach is to use dessicant dehumidification technology.This is widely used throughout the pharmaceutical industry and is a reliable method of achieving low levels of humidity in different areas of the manufacturing process. Levels below 5% RH can be achieved in various areas of the packaging space, or even in an area surrounding a tableting machine or coating drum.

Care needs to be taken when very low RH levels are required since the difference in vapour pressure between the room and operators will increase, leading to increased evaporation from the skin and the effect of evaporative cooling giving the impression of a lower ambient temperature.It is often the case that the dry bulb temperature needs to be increased by a few degrees to offset this effect.

Low levels of relative humidity can have several benefits for tablet making:

Improved reproducibility of results – more uniform quality

Reduced friability of powder during tablet compression

Improved appearance of coated tablets

Reduced waste due to powder clogging the machinery

Reduced maintenance and downtime

Improved packaging processes

Reduction in microbiological contamination

Reduction in static charge on equipment and products

Dessicant technology

To achieve low levels of RH, it is necessary to use a conventional refrigeration system as the first step in improving air quality.A refrigeration system is best for removing large quantities of moisture from the air before the RH level is reduce to low levels using a dessicant dehumidifier.For this reason a conventional system may be used to bring the RH of a complete facility down to 35-40%, and this may be acceptable for some of the process steps.Dessicant technology may then be used on individual specific process areas to achieve the required low levels of humidity for those areas.

A dessicant dehumidifier or dryer consists of a rotating wheel or drum that is impregnated with dessicant (typically silica gel).The gel is usually coated onto a corrugated substrate that gives a very high surface area to volume ratio, typically over 2000 m2 per m3 of air flow.The high surface area leads to very efficient moisture transfer, and the construction of the machine is such that a relatively small area of the rotating wheel is exposed to the air stream at any given time.The rotating dehumidifier may therefore be a relatively small item of equipment, compared for example with a refrigeration air handling system.Air leaving the dehumidifier is usually too dry for most applications and is therefore blended with another air stream to achieve the desired relative humidity level.As the wheel of the dehumidifier rotates, so the moisture laden section of the wheel passes through a section in which a flowing stream of heated air drives off the absorbed moisture through a vent, that typically discharges outside the building. Design of the rotating dehumidifier is such that the dessicant does not become over-laden with water at any given time – it is either dehumidifying incoming air, or being regenerated by a stream of heated air. Relative humidity levels as low as 1% at an ambient temperature of 25°C can be obtained by using a rotating dessicant wheel.

Room considerations

It is important when specifying dehumidification equipment to allow for the worst case ambient conditions.In the UK, for example, it is prudent to work on the assumption of a maximum temperature in the environment of 35°C and moisture removal rates of 16 g/kg of air.By erring on the high side, the investment in equipment can be made knowing that the required humidification levels will always be achieved.Retrofitting equipment that does not meet the required specification can be more expensive than the initial capital purchase.It is also important to make sure that all efforts have been taken to ensure that the building or area to be dehumidified is well sealed – this includes air locks, ceiling vents, and the minimising of door openings and material transfer areas.Specialist room construction is not normally required to achieve RH levels as low as about 20%, but for lower levels, the building and the dehumidification equipment should be designed together as a package to achieve the best possible results with the lowest capital cost.In doing so, other features such as HEPA filters and temperature/air flow control systems should be incorporated to achieve the best quality air for the working environment.

Final thoughts

The required level of relative humidity for production of pharmaceutical tablets is highly dependent on the nature of the powder raw materials and the desired product.Materials that are not particularly moisture sensitive may only require dehumidification to around 40% in which case conventional equipment will achieve the desired results.More usually at least some of the process steps will require much lower levels of humidity.In these cases, dessicant drying technology is to be preferred.The size of the equipment, and therefore capital cost, will depend on the materials used in the tablet production and the expected production rate.Dessicant dryers are, however, relative simple items of equipment with lifetimes in excess of 10 years.

]]>Thu, 12 Jul 2018 14:36:28 +0000https://www.lfatabletpresses.com/articles/water-soluble-binding-agents
The manufacturing of a tablet includes compressing a drug with several excipients. Mere compaction of a dry powder between two punches yields a tablet that easily crumbles.To achieve successful tablet production, the raw powder formulation is usually subject to granulation, a process which breaks down the large particles of powder into smaller particles of more uniform size.Wet granulation is generally preferred over the granulation of dry powders as it can achieve a fine powder that more easily flows into the dies of tableting machines.Wet granulation utilizes a liquid and a binding agent, and it is the binding agent that helps to hold the powder particles together as tiny granules.The liquid should be non-toxic and is preferably water, although various other solvents may be considered, such as propan-2-ol and ethanol for materials that are sensitive to moisture or heat. When a granulated mixture is subjected to compression, it results in the production of a tablet that is sufficiently hard to withstand the rigors of subsequent packing and transportation.

Certain natural and synthetic polymers and sugars are commonly used as binding agents.This article focuses on widely used water-soluble binding agents.Having said that, polymers are increasingly developed to solve specific problems associated with novel drug delivery systems.These include, for example, polymer-drug conjugates for a variety of drugs (insulin, peptides and lipids), to obtain clear soft gel capsules for transporting insoluble drugs, and as hydrogels for sustained release of topical drug. The binding agents that are discussed below divided for convenience into two categories (1) synthetic and (2) natural.

1. Synthetic water-soluble polymers

1.1Polyethylene glycol (PEG)

This polymer is synthesised by from ethylene glycol and has a lower polydispersivitiy index (PDI) than most polymers meaning that PEG has a reliable residence times in the body.It is soluble in water and organic solvents and is non-toxic, making it a widely used polymer in pharmaceutical products. The high hydrophilic nature of PEG enhances the physical stability of drugs and prevents aggregation of drugs in vivo, as well as during storage. It can be used to improve the plasticity of other binding agents, and may prolong disintegration times of tablets when the concentration is higher than ca. 5% by weight.PEG has been used as a meltable binder as an anhydrous binding agent where water or alcohol cannot be used.It is chemically easy to modify PEG and a variety of drug conjugates have been synthesised and applied as binding agents or drug delivery systems.

1.2Polyvinyl pyrrolidone (PVP, or Povidone).

This, the most widely used synthetic binding agent, is a water-soluble polymer having a molecular weight ranging from 40,000 to 360,000. It is synthesised by polymerisation of vinylpyrrolidone in water or propan-2-ol and is available in different graded based on molecular weights.Wet granulation with PVP having a molecular weight between 25,000 and 50,000 generally gives hard granules with good flowability, high binding and low friability.Another advantage of PVP is that is increases the dissolution of the active ingredient (API).For example, research has shown that paracetamol tablets formulated with 4% PVP 90,000 as binder, released the drug more quickly than tablets with gelatin or hydroxypropyl cellulose as binder. Soluble grades of PVP have been shown to improve the bioavailability of many poorly water-soluble drugs.As well as improving bioavailability of tablets, PVP can also be used to formulate drugs as glass solutions by hot melt extrusion (HME).Povidone and trimesters of citric acid can also be combined to obtain clear soft gelatin-like capsules of insoluble drug substances. Some grades of PVP are also useful for the preparation of sustained release tablets.

1.3Polyvinyl alcohol (PVA)

This polymer is synthesised by the polymerisation of vinyl acetate to give an acetate polymer which is then hydrolysed.The extent of hydrolysis and content of acetate groups affect the crystallizability and solubility of PVA in water.This polymer is also soluble in ethylene glycol, and n-methyl pyrollidone, and is therefore often in mixtures with these materials. PVA is often used in hydrolysed form as a gel for topical pharmaceuticals, in sustained release tablets, and as a stabiliser in emulsions.

1.4Other synthetic polymers

A number of water-soluble synthetic polymers have been trialled as binding agents or as the basis of drug-polymer conjugates for drug deliver systems.Whilst not yet widely used, their importance may grow for specific oral dosage forms.They include, polyacrylamides and poly-methyacrylamides (as carrier for drugs and bioactive molecules), divyinly ether-maleic anhydride (as antitumour agent), polyoxazoline (as adhesives or coatings), and various types of polyphosphates (used in tissue engineering).

2.Natural water-soluble polymers

2.1Starch

Starch is one of the earliest known binding agents to be used in tablet manufacturing. It is a white powder having no odour or taste. Chemically starch is mainly composed of two homopolymers of D-glucose:amylase, and branched amylopectin.Starch polymers have many functional hydroxyl groups and the material is therefore hydrophilic in nature.Native starches can be prepared from a wide variety of plant sources such as corn, potato and wheat.Careful preparation is required to achieve reproducible performance.Native starches tend to be highly viscous, to agglomerate, and have poor flow properties, making their handling difficult during the tablet manufacturing process.For these reasons, freshly prepared starch is now rarely used as a binding agent.

2.2Pre-gelatinized starch

Starch can be chemically and physically modified to improve its properties such as clarity and cold-storage stability.Maize, potato or rice starch can easily be hydrolyzed or partly hydrolyzed by heating with water.The process ruptures all or part of the starch structure, and after subsequent drying is used as a pre-gelatinized gel.Starch is also commonly modified by a hydroxypropylation process.The presence of hydroxypropyl groups on the starch molecules increases their water-holding capacity and reduces the re-association of starch chains. The result is a more stable starch gel.

Pre-gelatinized starch typically contains 5% free amylase, 15% free amylopectin and 80% unmodified starch.It is a widely used excipient in tablet making and functions as a binder, diluent and flow aid.It can be used in a concentration of between 5 and 75% as a binder for wet granulation, or for dry granulation at lower concentrations.

2.3Liquid glucose

Liquid glucose is a colourless to yellow-coloured viscous liquid that is obtained from corn starch.The process of manufacture includes partially hydrolyzing starch using an acid or enzyme. Being a viscous liquid with strong cohesive property, it acts as a good binding agent in tablet manufacture.

2.4 Cellulose ethers

Pure cellulose, which is a naturally polymer that occurs in plant fibres and is insoluble in both hot and cold water due to strong intramolecular hydrogen bonding.Cellulose can be chemically modified by controlled hydrolysis. This process yields a partially depolymerized form of cellulose called microcrystalline cellulose (MCC).Generally, this product has a polymerization degree less than 400. MCC and is useful in the preparation of tablets prepared by direct compression as well as wet granulation methods. Unlike other traditional binders that slow down the process of tablet disintegration, MCC acts both as a binding and disintegrating agent. Tablets containing MCC should not be exposed to high humidity conditions, which tend to soften the tablets. This form of cellulose is one of the most widely used tablet binders..

Further chemical modification of cellulose can produce water-soluble ethers, the most common of which are:

Hydroxypropylmethyl cellulose(HPMC)

Hydroxypropyl cellulose (HPC)

Hydroxyethyl cellulose (HEC)

Sodium carboxy methyl cellulose (Na-CMC)

These modified cellulose derivatives are used in a wide range of applications to enhance water retention and pseudoplastic behaviour, for their film forming properties and their ease of complexing with active drug ingredients.They are commonly used as binding agents, coating agents, emulsifying, stabilising agents and as tablet disintegrants.Of the synthetic binding agents, the derivatives of cellulose are perhaps the most common water-soluble binding agents used throughout pharmaceutical products.

2.5 Carnuaba wax

Carnauba wax is used in the pharmaceutical industry as a binder and coating material for tablets.It is produced from the leaves of the Copernicia prunifera palm grown only in Brazil. Carnauba wax is also known as palm wax or Brazil wax.Carnauba wax primarily consists of fatty acid esters. Coating tablets with the wax enables easier swallowing of the tablet. Carnauba wax has many other uses, including uses from car wax to dental floss. Carnauba wax is a safe, non-toxic and inert ingredient.

2.6 Guar Gum

This natural polysaccharaide is obtained from the endosperm of the guar plant.It is widely used as a binding agent in tablets and also acts as a stabilizer, thickening agent, emulsifier and suspending agent in liquid formulations.The swelling ability of guar gum is used to delay the release of drugs from oral dosage forms.

2.7 Pectin

Pectin is a mixture of polysaccharides, and is obtained from citrus peel or apple pomades, both of which are byproducts of juice production.Pectin is widely used as an additive in convenience foods, and as a binding agent in the manufacture of tablets along with hydroxymethyl cellulose.Pectin also has several unique propertiese which have enabled it to be used as a matrix for the entrapment and /or delivery of a variety of drugs, proteins and cells.Pectin has been shown to reduce cholesterol in a diverse group of subjects, and has been reported to remove lead and mercury from the gastrointestinal tract and respiratory organs.

2.8 Xanthan Gum

Xantham is a free-flowing powder soluble in both hot and cold water to give a viscous solution at low concentrations.

]]>Tue, 26 Sep 2017 13:50:49 +0000https://www.lfatabletpresses.com/articles/tablet-making-humidity-required
Poor environmental control, particularly in terms of air humidity can directly affect the pharmaceutical production line in a number of ways. Levels of humidity below 45%RH will allow electrostatic charges to build up in machinery and materials. This can have major implications where flammable solvents are used in the process, so that electrical bonding between machines becomes important. Low humidity can also cause the product to dry out, affecting its performance. Build up of charge on powders can result in poor power flow, and charged products can cause them to stick to each other, leading to packing problems.

High humidity can also cause products to absorb moisture during production and final packaging. Some antibiotic tablets, for example, are degraded and their effectiveness reduced, if moisture is absorbed. Where the product is long-term moisture sensitive it will degrade over time when packed under the wrong conditions. Moisture sensitive formulations are often coated in a thin polymer film to prevent the ingress of water from the atmosphere. But the coating of polymer films itself requires careful environmental control to ensure that a smooth uniform finish can be achieved and that the outer surface of the tablet can be printed with water-soluble ink.

The issue of humidity is therefore an important one for the tablet manufacturer, but also complex, since there may well be different requirements for the moisture content of atmospheres at different steps in the manufacturing process. Therefore, the control of the production environment is becoming more critical as product development moves forward.

Conventional humidification control

Air conditioning and handling equipment based on refrigeration cycles – heating ventilation and air conditioning (HVAC) systems, is generally built to condition working environments so as to maintain levels of relative humidity between 40 and 60%, with temperatures around 21 – 25°C. It is felt that the environment needs to be controlled for personal comfort, and it is assumed that the product will also be stable in this wide-ranging environment. It is not until low productivity levels are found, and production problems are traced back to the temperature and humidity control, that the importance of the right equipment can be truly seen. It is important to control the humidity and temperature of the atmosphere in all of the tablet production areas. Indeed environmental control within an individual production machine such as a rotary tablet press can also have critical bearing on the quality of the final product.

Specific requirements

Wet granulation processes can be carried out in humid environments since the formulations contain water. By contrast, dry granulation, which is often necessary for moisture sensitive APIs such as antibiotics, requires the relative humidity of the surroundings to be as low as possible to give the materials the best chance of surviving the production process. Generally speaking tablet compression machines require the products to be dry and low humidity of the surrounding air is beneficial, especially if the drug or formulation excipients are sensitive to moisture. However, there is also a danger in making the air too dry in that electrostatic charges may build up in the powders, causing flow problems and materials to clog flow lines. Poor filling of dies can then lead to defective tablets. The required level of humidity for the compression process is therefore largely governed by the degree of hydrophilicity of the components in the formulation. There is no single answer to the required level of humidity for tablet making.

When tablets are coated with aqueous based polymer films or with sugar coats, extremely tight control of air humidity is required to ensure that the coating does not dry too fast or too slowly. There are also pharmaceutical printing processes that require control of humidity between 95 and 98%RH, with temperature control to better than 1ºC, to prevent water based inks from drying during processing.

What technologies can give the required humidity?

Relative humidity levels below 40% can be achieved with a rotary dessicant dryer. These machines have been in use for many years and can be sized according to the work area that needs to be dried. They function by passing a stream of ambient air through a solid dessicant (typically silica gel) located within a rotating wheel or bed. The exit air from the rotary dryer may have a relative humidity of 1% or lower, and it may be necessary to blend this air stream with another to achieve the required level of humidity for the particular manufacturing equipment or process. Flow control is therefore important. Water that is absorbed from the air by the dessicant is released by the dessicant bed rotating into a stream of hot air. The resulting wet air is usually vented outside the building.

If the relative humidity of the environment is too low, for example in the case of the area where tablets are printed with water-soluble inks, it may be necessary to increase the humidity of the atmosphere. There are several commercial humidifiers that can be used for this purpose. Electrode boiler steam humidifiers are expensive to run but are good means of ensuring high humidity. Savings can be made if process steam is available in the facility as this can be used to indirectly heat pure water, thereby saving in the cost of electricity needed for raising steam. More savings still can be made by using a cold water humidifier as the water does not need to be heated.

Cold water humidifiers have had a bad press in the past because of fear about the safety in respect of Legionella or other bacterial spores. The UK Health and Safety ACOP L8 document states that, provided the systems meet all the requirements of the L8 code of practice, there is no more significant risk than using steam systems - in some cases less. It is also often assumed that, because a system is steam based, there is no risk. Unfortunately, this may not always be the case.

The major advantage of cold-water humidifiers is that they use less than 10% of the energy required by steam humidifiers. Also, because the principle of cold-water humidification is adiabatic, free cooling of the atmosphere can be achieved. This can result in cost savings, not only in winter, the main humidification season, when the return air from the production area is warm and typically large quantities of fresh air are used to give free cooling, but also in the summer, when the outside ambient temperatures are high, the air can be cooled by up to 6ºC by the humidifier.

Control and maintenance

In deciding what level of humidification is required and the technology required to achieve this, attention has to be given to the method of control. In pharmaceutical R&D, the control of humidity and temperature can have major implications in bringing a product to market. This may be from a production point of view, where the yields are often low until the humidity and temperature are accurately controlled; pharmaceutical coating applications are a prime example of this, as is stability testing of pharmaceutical products.

In both of these areas, the control of the environment has been found to be critical. Poor control can give variations in coating, making it necessary to reject entire production batches, often amounting to thousands of pounds worth of stock. More importantly, falling outside of control parameters in long-term stability testing will lead to a restart. This can put weeks, or even months, on to the research and development time of a new product, enabling competitors to launch similar items sooner and gain that all important competitive advantage.

In addition to control, the maintenance of equipment must be factored into the cost of humidification or dehumidification. Installation of such equipment requires a full understanding of, not only the application, but also the design and control of the process. Selection of the right equipment for the particular application and the support of the equipment once installed are critical to the long-term reliability and operation of the system. When considering the how the right level of humidification is to be achieved for tablet making, it would be most beneficial to consult a specialist environmental control expert instead of a regular HVAC engineers.

]]>Tue, 26 Sep 2017 13:43:16 +0000https://www.lfatabletpresses.com/articles/keep-moisture-out-of-tablets
There are many factors to be considered in the quest for drug quality assurance.These include environmental moisture, stability and packaging solutions.If all of these aspects are addressed throughout the manufacturing and storage processes, the product can be isolated and protected from all possible threats to quality and efficacy.

In addressing the issue of moisture, consideration should be given to the formulation and coating of the product (i.e., capsule or table), to the transport and storage of the product from manufacturer to consumer, and to the treatment and storage of the product by the patient.There are safeguards that can be taken at each step to minimise degradation of the product by ingress of moisture.Long-term stability testing of stored material has been the subject of much research with design of primary packaging and choice of dessicants being considered the key defences against degradation and loss of efficacy.The design and composition of the drug product itself can also affect the moisture sensitivity of the final dosage form and needs to be considered from the outset.

Inside the tablet

Excipient selection and core formulation do influence the stabiliity of moisture sensitive drugs and compounds.Water can be present in formulations as a free and mobile form which can react with other materials, or in a bound form that is essentially unreactive.For example pre-gelatinized maize starch 1500 has a relatively high moisture content of 14%, as measured by loss on drying.It is, however, less reactive than other excipients with lower moisture content, e.g., mycrocrystallince cellulose or dicalcium phosphate.Many studies have shown that Starch 1500 improves product stability, and this is believed to be by the material acting as a moisture scavenger, sequestering free water that may be present in the formulation.

Film coating

The right film coating formulation can provide a functional barrier to improve the stability of moisture sensitive substances, by reducing the moisture vapour transmission rate (MTR).While conventional hydroxypropylmethyl cellulose(HPMC) based coatings do impeded the ingress of moisture when compared with a uncoated tablet, it has been shown that coatings that utilize polyvinyl alcohol (PVA) as the film-forming polymer show significantly less ingress of moisture. Opadry amb II, a high performance moisture barrier film coating and marketed by Colorcon, is the first fully formulated PVA-based immediate release system without polyethylene glycol (PEG) that delivers the three-fold advantage of high productivity, low impurity levels and a superior tablet finish. Tablets coated with Opadry amb II exhibit a high-gloss, quality appearance with well-defined logos.

Packaging

Several studies have shown that film coating may be more important than the final packaging of oral dosage forms.Colourcon, for example, assessed the degradation of three different packaging configurations:Alclar blisters, aluminium foil-foil and high density polyethylene bottles with dessicant.Clavulanic acid/amoxicillin tablets were tested and the uncoated and HPMC-coated products showed marked degradation under all packaging scenarios, whereas tablets coated with Opadry amba II showed superior stability in all packagings.Such tests affirm that film coating offers marked benefits in preventing moisture from degrading tablets.The benefits of the right film coatings become more important when consideration is given to what happens once the pharmaceutical product reaches the patient.After the dosage form has been dispensed by a pharmacist, it is not unusual for the tablets to be transferred out of their packaging to a pill sorter, or for a patient simply to place their medication into any convenient container – or even a clothing pocket.Under such circumstances, the longevity of a product is highly dependent on the formulation itself and the application of one or more protective coatings.

2) We highly recommend using an engine hoist along side a heavy duty tow strap or chain that is rated to handle significantly more than the weight of your machine. Attach the strap or chain to the top of the flywheel (the largest diameter wheel on the press which is located on the right side of the press if you are looking at it from the front of the machine. Once the chain or strap is securely attached you will need to connect it to the engine hoist. Lower the boom of the engine hoist to an appropriate height and attach the strap or chain to its hook whilst keeping everything taut.

3) Next, SLOWLY begin to raise the press using the engine hoist. We recommend having one person do the lifting and one person steadying the press as it is being raised making sure to keep hands and feet clear of the press.

4) Once the press is swinging freely you should stop lifting and lock the hydraulic lift. Once it is secured you can begin to move the press to the table on which you wish to install it making sure to move slowly and keeping hands and feet clear.

5) After moving the press close enough to the table you may then start raising the press, again slowly and making sure that your hands are never in between the press and table.

6) Once the press is at the correct height to be able to lower it onto the table you may then move the engine hoist closer to the table until the press is hanging above it.

7) After which simply release the lock on the hydraulic lift and SLOWLY lower it onto your work table. Again we recommend having an extra set of hands steadying the press and turning into the desired position while it is being lowered.

]]>Tue, 12 Sep 2017 15:47:35 +0000https://www.lfatabletpresses.com/articles/validation-of-dry-mixing-and-tablet-production-processing
1. What is validation and why is it necessary?

Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.This article focuses on the process of dry mixing of powders, as one of the steps in producing tablets.Validation can therefore be applied to the dry mixing process itself, as well as the overall manufacture of tablets.

2.What are the benefits of validation?

A successful validation of process and equipment provides a high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.

Successful validation of a process can result in a reduction of sampling and testing procedures and hence fewer product rejections and the need for retesting. The lower rejection rate leads to cost-saving benefits.For compliance to current good manufacturing practices, validation is essential.

3.How important is validation of dry mixing in the tablet production process?

Dry mixing is usually the first step in tablet production and it is therefore of paramount importance that the quality of mix is of the highest standard if high quality tablets are to be produced. All of the steps in tablet production are of course important, and the manufacturing company should not lose sight of all of the process steps, and that to validate each one will lead to the best outcome.The process steps and suggested validation protocols for each step are outlined in the table below.

4.How is dry mixing validated?

The mixing of API and excipients is perhaps the most critical step in the solid dosage form preparations that affect the content uniformity of the finished product.Mixing can be carried out using :

V cone blenders

Double cone blenders

Drum mixer

Ribbon blenders

Conical screw mixer

Tumble blender

Convection (planetary mill or high high intensity mixer or fluidized bed mixer)

Each type of blender is usually validated or qualified at different stages, for example:

During design or development

Documented verification of the design of equipment and manufacturing facilities.

Installation Qualification

Documented verification of the system design and adherence to manufacturer’s recommendations.

Operational Qualification

Documented verification of equipment or system performance in the target operating range.

Process Performance Qualification

Process validation can be defined as means of challenging a process during devlopment to determine which variables can be controlled to ensure the consistency production of a product or intermediate. It is based on the concept that the processesemployed has been optimized, so that the data generated through the testing program may be considered credible and evaluated for consistency as well as relevance.

Change Control

Equipment must be re-validated if significant changes are made to the equipment or the way that it is used.

Each type of blender presents different issues in terms of validation. The most important parameters to be monitored are:

1.Particle sizes and uniformity of the original materials (API and excipents).Handling of material is key to obtaining valid content uniformity results.Sample size taken should be equivalent to the weight of a single tablet.

2.Mixing speed- mixing of drug and excipient requires more intense mixing than adding the lubricant to the final blend.

3. Mixing Time – this depends on mixing technique and speed.

4. Equipment – note that the bulk density of material will affect the capacity of the equipment.In validating mixing equipment, attention should be given to the following:

Operating criteria must be adequate

Spares should be available

Equipment should be easily maintained

Equipment should not disseminate dust

Capital and running costs should be as low as practical

Equipment must have non reactive surfaces

Mixing speeds must be adequate.

5. Uniformity of blended material.

This parameter is perhaps the most important to measure.It is not easy, however, to define as it is both a physical (size, shape), and chemical (composition) property.Blend and can therefore be problematic in quantifying.Many papers and conferences have indeed been devoted to the subject of powder blend uniformity and a paper reviewing the subject was published in February 2017*.A protocol for measuring blend uniformity should be agreed with the Quality control department and analytical methods adapted according to the type of drug being produced. At the end of a mixing batch, samples should be taken and passed to a QA department to check uniformity of chemical composition, e.g., measure the concentration of API in each sample,measure bulk density and particle size analysis (sieve analysis).

Some techniques have been developed to measure uniformity during the mixing process itself. Most notable of these are near infra-red spectroscopy, Raman spectroscopy, and Microscopic FTIR mapping.

5.What are the basic validation requirements?

In evaluating a mixing process it is important to consider the worst case in all measurable parameters.These include maximum and minimum mixer load, maximum and minimum speed (rpm), maximum and minimum mixing time.In each case samples should be taken of the mixture that represent the whole of the mixed material within the equipment. A sampling protocol should be agreed by all parties. For example, samples should be taken from the top, middle and bottom of the mixed bed of material as illustrated below. Duplicates should be taken and analysed to avoid sampling bias.

For initial qualification or validation of equipment the following are the minimum requirements:

Equipment name, make and model No. shall be recorded.

Location for the installed equipment should be checked.

A record should be made of all the required utilities (e.g., electricity, compressed air, gases, water).

Any deviation observed while following the installation procedure should be recorded in case corrective action is required.

After checking all the specifications as mentioned in the selection criteria, service engineer shall commission the equipment.

Authorized validation team shall carry out installation checks.

For operational qualification of the mixer the following are required:

After completions of successful installation qualification initiate the actual operation of to ensure that machine is operating within specification.

Check the operation qualification parameters against the manufacturers specifications.

Document any deviation from specifications.

The Quality head and the department head should decide whether deviation is acceptable or not.

To validate mixer performance:

Load the materials to be mixed in the mixer

Start the mixer and rotate it for the time as mentioned in the BMR.

After completion of mixing switch OFF the mixer and separate out the drum.

Collect the sample as per sampling procedure.

Send the samples to Quality control dept. for blend uniformity, bulk density and sieve analysis.

Powders and granules can be used as dosage forms in their own right, but by far the greatest use of granules and powders in the pharmaceutical industry is as an intermediate during the manufacture of compressed tablets. Such products begin with the starting materials – the active pharmaceutical ingredient, API, and various excipients. In addition to transporting the active drug to the area in the body where the drug is intended to exert its action, excipients play an important part in the manufacturing process. They may also be important for keeping the drug from being released too early when ingested – in places where it could damage tender tissue and create gastric irritation or stomach upset. Excipients include diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives. Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance, especially in children. Although technically "inactive" in a therapeutic sense, pharmaceutical excipients are critical and essential components of a modern drug product. In many products, excipients make up the bulk of the total dosage form.

Each of the starting materials, i.e., API and excipients may be supplied initially as powders with different particle sizes and densities, and the first task in the manufacturing process is to mix them so that they can be fed forward to a granulation process. Granulation is usually required to increase the average particle size of the powders so as to create material that freely flows into the tablet making machinery. The granulation process at best will create a well-mixed material but it requires careful control on the part of the manufacturer to ensure good mixing, and often some separation of the different materials can occur, on account of the different particle sizes, shapes and densities of the starting materials. Indeed, even before the granulation process takes place, some separation or segregation of the different materials can occur. This is particularly the case if the mixed materials have to be conveyed a significant distance between the mixing stage and the granulation stage, e.g. by a pneumatic or vacuum system.

Vacuum-conveying technology is commonly used in the pharmaceutical industry to move materials through the processing line, blend ingredients in various solutions, and handle tablets. Because it is an enclosed system, vacuum conveying is safe, hygienic, and the preferred solution for many applications. The vacuum conveying of powders and granules, however, must be performed well to avoid segregation, the separation of ingredients that results in an uneven mixture.

Segregation – a costly problem Segregation during the conveying of powders is a significant problem for the pharmaceutical industry. Indeed, particle segregation is a common problem in many bulk storage systems and its presence creates serious quality control issues. Segregation creates inconsistent batches that can cause dosage variations in pharmaceuticals, significant weight and flavour variations in packaged foods and gas flow problems in chemical reactors.

There are more than a dozen easily identifiable segregation mechanisms that result in out-of-spec products, but the five most common segregation mechanisms -- sifting, angle of repose, fines fluidization, air currents and chute trajectory – are responsible for more than 80 percent of segregation problems in solids handling and storage systems.

Sifting segregation

This is mostly likely to occur in a mixture containing free-flowing particles of significant size variation – typically differences in the mean diameter of 3 times or more. Inter-particle motion, often brought about through vibration, causes the finer components to sift through coarse components. All bins, batch blenders and chutes have the potential for sifting segregation problems. Because it uses an air stream to move particles, vacuum conveying also presents the risk that ingredients will separate through sifting. Small particles will pass through the mixture of larger particles. Dense particles will drop below less dense particles, and stratified flow can occur.

Angle of repose segregation

The angle of repose of a granular material is the steepest angle of descent or dip relative to the horizontal plane to which a material can be piled without slumping. At this angle, the material on the slope face is on the verge of sliding. The angle of repose can range from 0° to 90°. The morphology of the material affects the angle of repose; smooth, rounded grains cannot be piled as steeply as can rough, interlocking grains. The angle of repose can also be affected by additions of solvents; if a small amount of water is able to bridge the gaps between particles, electrostatic attraction of the water to mineral surfaces will increase the angle of repose. Angle of repose segregation occurs when particles deposited with greater angles of repose form a steep pile under the deposition point while the ones with lower angle of repose roll away from that point.

A mixture containing components that are cohesive or rough-surfaced are particularly prone to angle-of-repose segregation. Rotating shell-type blenders, stock piles and bins are susceptible to this mechanism.

Fluidization segregation

Fluidization segregation can occur when a mixture contains a large portion of light or fluffy free-flowing, fine component, enough to form a layer, and smaller portion of a relatively coarse, heavier component. The larger component easily penetrates the fluidized fines, pushing the fines layer to the top of the bin or vessel. Fluidization is especially active in air blenders, high-speed ribbon blenders, bins and piles.

Air current segregation

The finer particles in a mix are susceptible to be airborne in the presence of airflow. These very fine particles migrate to the walls of a vessel wall or toward a dust collection system. If the fines are a minor component of the mixture or are cohesive, migration can be significant.

Chute trajectory segregation

This type of segregation occurs as a result of particles having different coefficients of friction and results in different discharge trajectories as the mix slides down a chute. It can occur in the feed hopper of a tablet making machine. High friction coefficient materials usually contain fine particles and slide more slowly down a chute than low friction materials. This results in different discharge trajectories. Particles with high friction coefficients show lower discharge angles the end close to the chute, whereas the trajectory of particles with low coefficients of friction deviate further away from the chute.

Many pharmaceutical products depend on an accurate powder-to-powder ratio, and end-product quality is in jeopardy if segregation is not mitigated. The problem should be addressed in advance because much raw material may be wasted even if the incorrect mixture is detected before end processing.

Solutions to powder segregation

There are some simple, practical steps that can help to reduce these segregation mechanisms. The following are suggested modifications of equipment or operating procedures, both of which do not usually require large capital expenditures.

DO use a bin with tall cylindrical section that provides flow at the walls.

DO use a mixing device at the centre for charging a multiple-outlet bin. This will create uniform, symmetric segregation.

DO proportion and mix badly segregated materials just before processing using as little surge capacity as possible.

DO use a tangential entry for pneumatically conveyed fluidizable solids or install a cyclone at the bin top that uses a deflection plate.

DO use inclined open chutes to decrease air entrainment in ascending solids. This not only reduces fluidization entrainment, it also reduces dusting.

DO premix liquid with coarser particles before adding finer components if sifting or angle of repose segregation is likely to be present.

DO use blenders that remix top-to-bottom during hopper discharge or use static stream blenders below belt discharge points to remix segregated solids.

DON’T split material from a belt conveyor into various bins since the belt may segregate the materials.

DON’T use a non-symmetrical, multiple-outlet bin.

DON’T use a uniform velocity mass-flow bin to cure fluidization-type segregation. It will only make it worse.

DON’T use freefall chutes to transfer materials with different friction angles unless there is a mixing device downstream.

DON’T charge a mixture of fine fluidizable powder and non-fluidizable coarse particles from a pneumatic conveying line using a vertical downspout.

Lean-phase versus dense-phase conveying Segregation is not exclusively a powder- and bulk-conveying problem. It can occur when a product is transferred from a mixer to a feeder or during mix discharge at the end of the conveying line, where heavier materials drop to the bottom of the mixer. But manufacturers can take steps to optimize the conveying process.

With pneumatic or vacuum conveying, processes known as lean-phase conveying and dense-phase conveying can occur. During lean-phase conveying, a great amount of air is mixed with a small quantity of powder, the outcome of which is which high air velocity and high powder velocity. In lean-phase conveying, the volume and speed of air are high enough to keep particles continuously moving in suspension. These factors also increase the likelihood of segregation because light and less-dense particles flow faster than heavy and dense particles, which may lead especially to sifting or airborne segregation.

Dense-phase, or plug-phase flow conveying occurs at a slow speed. A low flow rate of air in the conveyer moves material in plugs separated by small distances. This conveying technique can create fluidization, which converts powdered material into a well-mixed fluid-like state. Sometimes used at the suction point and discharge point, fluidization lets air pass through porous materials. Fluidized material is moved in waves at a slower speed than the compressed air.

Dense-phase conveying maintains the desired ratio of the mixture much better than lean phase conveying. Air speed is not as high in dense-phase conveying as in lean-phase conveying, so that the separation or segregation resulting from particle-size and weight variation is lower.

Empirical testing improves quality and content Although segregation is a common problem with powders and granules, no universal solution exists for all materials or formulations. Each conveying application has to be considered in its own right. Dense-phase conveying is the best strategy to mitigate segregation, but it cannot be applied in every case. Different materials behave differently and should be tested and evaluated before the conveying process is adjusted. Likewise, different mixes of ingredients will require different adjustments to the conveying application.

Pharmaceutical companies test their mixes regularly to ensure consistent content and high product quality. The conveying line should also be assessed, to determine how process variables affect the transfer and segregation of material. For example, elements such as piping (e.g., pipe ends, bends, and sharp edges) may change the material’s flow characteristics and affect segregation. The whole conveyance system should therefore be assessed before developing a solution.

Developing the optimal solution New conveying products and systems will help pharmaceutical manufacturers reduce segregation. PIAB, a Swedish supplier of vacuum conveying equipment, is currently developing a constant-speed vacuum conveyor. Setting the vacuum pump that provides flow in the conveyor at a consistent speed may ensure that, regardless of the product being conveyed, segregation would be an easier problem to solve. Typical vacuum pumps are affected by the pressure drops that occur throughout a system, but the pump PIAB is developing compensates for pressure drops by changing the flow (i.e., speed).

]]>Tue, 20 Jun 2017 06:06:18 +0000https://www.lfatabletpresses.com/articles/preventing-cross-contamination-in-pharmaceutical-production-process
There are several ways to prevent cross contamination during the production of pharmaceutical products. The list below is a guide to help minimise cross contamination between products.

General

Before starting, line clearance should be performed as per the standard operating procedure (SOP) of the company. Use a checklist and record that clearance has been completed.

Check to see if any starting materials are missing, check that previous record documents are complete and there are no previous product residues or product itself remaining.

Practice a closed system when handling the materials (i.e., do not handle more than one set of materials at a time).

Do not process more than one product in the same area during production.

Check that every material is free from microbial or any other form of contamination.

Before using, remove the outer wrapping of the packaging material to help reduce contamination.

Before filling, visually check to see if the containers are clean.

Packing should be carried out with physical space between the packing lines.

Ensure proper and validated production system is in place.

Do not handle with bare hands the product or any items of equipment that will be in contact with the product.

Process control can be done in the production area but it must be cleaned to prevent any contamination of the product.

After production, follow the protocol for cleaning and maintenance of the equipment ensuring that the appropriate cleaning materials are used.

Cleaning materials should have labels on them to ensure that they can be clearly identified, and are different from that of the product.

Products that are identified for special circumstances should be reintroduced only when investigation and clearance is provided by the authorized personnel. All incidents should be recorded.

Repair and maintenance of the equipment should not have any impact on the quality of the product.

Clothing

Personal clothing should be of high quality. It should be appropriate and acceptable in the work area.

Opt for linen, as this is a non-shredding type of material.

Wear clothing that lessens or minimizes the exposure of body parts.

Routinely wash your hands.

It is important to wash clothes that have come in contact with sensitive products separately from other clothes.

Clothing should not be exposed to or contaminated by cleaning agents.

Use appropriate personnel protective equipment when applicable.

Use dedicated protective equipment for antibiotics, beta lactum, cytotoxic, hormones and drugs that are manufactured using live microorganisms.

Clothing is preferred that is able to be worn repeatedly or that can be laundered repeatedly without deteriorating.

Utilities

Water should be appropriate for use in the manufacturing of pharmaceutical products. Regular checks should be made on the quality of any bulk supplied water (tap water)

Chemical and microbial limits in the water should be appropriate for the intended use.

Steam

Use a steam generator whenever possible for cleaning.

Steam should be free of additives.

Compressed Air

Use filtered air and ensure that the filter is regularly checked and replaced, as per SOP.

Sanitation and cleaning

It is important to practice proper hygiene and sanitation controls in every level of the manufacturing process.

Cleaning materials, pest control chemicals and sprays, chemical solutions and equipment lubricants should not come in contact with the product. Use suitable products to minimize the risk.

Prevent cross contamination by carrying out regular maintenance of equipment as per the company guidelines.

Products that contain beta lactum, hormone, cytotoxic and antibiotics should be packed in a dedicated area or at least in different area to other products.

Active raw materials of beta lactum and similar can be transported with other active materials, the packed finished products can be transported with other non-active finished product.

If spillage or contamination occurs, discard the whole batch.

It is important to label containers clearly. This includes containers for raw materials, in-process and partially processed materials.

Label any empty containers with ‘cleaned’ or ‘to be cleaned’. Also label any empty containers with what previous product was placed in the container.

If beta lactum, cytotoxic, hormone or antibiotics are manufactured with other products in the same building it is vital to ensure that cross-contamination is prevented. Ideally this should be done by using a separate facility or dedicated machinery or equipment for the different products.

Check the name, address and other details required on the shipper label for any overprints or errors, affix one label on the outside of the box and insert a copy of the same in the box for the shipper.

Check the 5ply outer box for any dirt, tears or moisture damage.

If any defects are discovered during the packing process, stop the process and solve the problem. Check the all items packed in the previous hour to make sure that all packed goods are okay.

Resume the processing and perform all the in-process checks after solving the problem.

Arrange the finished items on a pallet for checking and verification by the supervisor.

After packing is complete, reconcile all the packing materials and document all these in the BMR.

Return all the excess unused packing material to stores, as per SOP for return of packing and raw materials:

A store person should carry out the reconciliation of returned materials.

The store person should compare the weight of material received and the actual consumption. If there is a difference in weight, this needs to be recorded, preferably as a percentage loss.

If the variation after reconciliation of active raw material is more than 0.5%, inactive material more than 1%, or volatile solvent more than 2% of the received quantity, further investigation should be instigated by the store personnel.

Packing materials returned to stores should not have a variance of more than 1%.

If an abnormal loss is recorded, the heads of stores, QA and QC departments should be informed.

Transfer the packed goods to shipping once approval has been granted by the QA department.